Trifluoroethoxybenzoic acids of the formula [I] above are useful as intermediates in the pharmaceutical industry. For example, 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid [III] is the key intermediate for the synthesis of the antiarrhythmic drug Flecainide [IV] and pharmaceutically acceptable salts thereof ##STR2##
(Banitt, E. H. et al., J. Med. Chem. 18:1130 (1975) and 20:821 (1977); Leir, C. M. GB 2 045 760A, (1980) and The Merck Index, 12.sup.th Edition, 4136).
It is known that (2,2,2-trifluoroethoxy)benzoic acids [VII] can be obtained by the reaction of hydroxybenzoic acids of the general formula [V] with 2,2,2-trifluoroethyl triflate [VI] according to Scheme 1 (Banitt, E. H. et al., J. Med. Chem. 18:1130 (1975)). ##STR3##
This method requires the use of trifluoroethyl triflate [VI] which is costly and not easily available commercially.
Another method involves the oxidation of the acetyl group of trifluoroethoxyacetophenones with hypochlorite as shown in Scheme 2 (Lair, C. M., GB 2045 760A). However, partial halogenation of the benzene ring may occur in this process, thus making it difficult for production of the (2,2,2-trifluoroethoxy)benzoic acids [I] as pharmaceutical precursors. ##STR4##
There is only one reported example of copper assisted fluoroalkoxy-de-halogenation of a 2-bromo-1-naphthalenecarboxylic acid derivative (Wrobel J. et al., J. Med. Chem. 34, 2504 (1991)). This example is very specific since it describes the de-halogenation of an active halogen, i.e. bromine, which is also located in a highly activated ortho position to a carboxylic group.